Folate Intake and Markers of Folate Status in Women of Reproductive Age, Pregnant and Lactating Women: A Meta-Analysis

Table 2

General characteristics of the included studies and effects on the biomarkers of folate intervention in women of childbearing age, pregnant and lactating women, with respect to the control/placebo according to the original paper.

Author, year	Country	Population (𝑛. included)	Description of supply	N. in intervention (FA) and in control groups (P) at latest time	Study design	Biomarkers reported	P value
Adank et al., 2003 [24]	New Zealand	Childbearing age women (239)	Folic acid capsule = 400 𝜇g/day.; Folic acid capsule = 2800 𝜇g/week.; Placebo capsule	FA (400) = 36; 𝑃=44	Double blind.; Duration: 12 wks.; Dietary assessment	RBC folate (nmol/L) (Microtiter technique, L. Casei).; Plasma homocysteine (𝜇mol/L) (fluorescence polarization immunoassay).	<0.001; <0.05
Brouwer et al., 1999_1 [25]	Netherlands	Childbearing age women (144)	Folic acid tablet = 250 𝜇g/day (500 𝜇g folic acid and a placebo tablet every second day).; Folic acid tablet = 500 𝜇g/day.; Placebo tablet.	FA (250) = 50; FA (500) = 45; 𝑃=49	Double blind, 2 containers of indistinguishable tablets: one red marked, one yellow marked.; Duration: 4 wks.; Dietary assessment	RBC folate (nmol/L) (Imx automated immunoassay system).; Plasma folate (Imx automated immunoassay system).	FA (250): ^a <0.01; FA (500): ^a <0.001; FA (250): ^a <0.001; FA (500): ^a <0.001
Brouwer et al., 1999_2 [26]	Netherlands	Childbearing age women (144)	Folic acid tablet = 250 𝜇g/day (500 𝜇g folic acid every the 2nd day).; Folic acid tablet = 500 𝜇g/day.; Placebo tablet.	FA (250) = 50; FA (500) = 45; 𝑃=49	Double blind, 2 containers of indistinguishable tablets: one red-marked, one yellow-marked.; Duration: 4 wks.; Dietary assessment	Plasma homocysteine (μmol/L) (HPLC and fluorimetric detection)	FA (250): ^a <0.01; FA (500): ^a <0.001
Cuskelly et al., 1996 [27]	UK	Childbearing age women (49)	Folic acid capsule = 400 𝜇g/day.; Folic-acid-fortified foods plus 400 𝜇g/day (FA-f).; Dietary folate plus 400 𝜇g/day (FA-d).; Dietary advice (DA); Control group: no treatment	FA = 9; FA-f = 6; FA-d = 10; DA = 7; 𝑃=9	Duration: 12 wks mos.; Dietary assessment	RBC folate (μg/L) (microbiological assay)
Daly et al., 1997 [28]	Ireland	Childbearing age women (110)	Folic acid tablet = 200–400 𝜇g/day.; Placebo tablet	FA (100) = 22; FA (200) = 28; FA (400) = 26; 𝑃=19	Double blind, identical tablets.; Duration: 24 wks	RBC folate (𝜇g/L) (microbiological assay)
Daly et al., 2002 [29]	Ireland	Childbearing age women (110)	Folic acid tablet = 200–400 𝜇g/day.; Placebo tablet	FA (100) = 21; FA (200) = 28; FA (400) = 26; 𝑃=19	Double blind, identical tablets.; Duration: 10 wks	Plasma homocysteine (𝜇mol/L) (automated fluorescence-polarization method).
Lamers et al., 2004 [30]	Germany	Childbearing age women (144)	Folic acid capsule = 400 𝜇g/day.; [6𝑆]-5-MTHF capsule = 416 𝜇g/day.; [6𝑆]-5-MTHF capsule = 208 𝜇g/day.; Placebo capsule	FA = 34; Low MTHF = 32; High MTHF = 35; 𝑃=34	Double blind, hard gelatine capsules; Duration: 24 wks	Plasma homocysteine (𝜇mol/L) (immunoassay on AxSYM analyser).	FA: ^a <0.01; Low MTHF: ^a <0.01; High MTHF: ^a <0.01
Lamers et al., 2006* [18]	Germany	Childbearing age women (144)	Folic acid capsule = 400 𝜇g/day.; [6𝑆]-5-MTHF capsule = 416 𝜇g/day.; [6𝑆]-5-MTHF capsule = 208 𝜇g/day.; Placebo capsule	FA = 34; Low MTHF = 33; High MTHF = 35; 𝑃=34	Double blind, hard gelatine capsules.; Duration: 24 wks.	Red blood cell folate (nmol/L); ({(whole blood folate × 100) – (plasma folate × (100 – hematocrit))}).; Plasma folate (nmol/L) (microbiological assay)
Fohr et al., 2002 [31]	Germany	Childbearing age women (163)	Folic acid capsule = 400 𝜇g/day.; MTHF (racemic mixture) capsule = 480 𝜇g/day.; Placebo capsule	FA = 51; MTHF = 52; 𝑃=57	Double blind.; Duration: 8 wks.	RBC folate (nmol/L) (immunoassay kit for IMx analyser).; Plasma folate (nmol/L) (immunoassay kit for IMx analyser).; Plasma homocysteine (𝜇mol/L) (reversed-phase HPLC).
Green et al., 2005 [32]	New Zealand	Childbearing age women (73)	75 g powdered milk daily.; Fortified milk = 375 𝜇g folic acid/day.; Control milk	FA = 36; 𝑃=37	Double blind.; Duration: 12 wks.; Dietary assessment	RBC folate (nmol/L) (from whole blood folate by subtracting plasma folate and correcting for hematocrit).; Plasma folate (nmol/L) (microtiter technique, chloramphenicol resistant, L. Casei).; Plasma homocysteine (𝜇mol/L) (Imx analyzer).
Ellison et al., 2004 [33]	UK	Pregnant women (30)	Folic acid capsule = 400 𝜇g/day.; Control group: no treatment.	FA = 15; 𝑃=15	Duration: 24 wks.	Plama folate (ng/mL).; Plasma homocysteine (μmol/L) (enzyme immunoassay).	<0.05
Lira et al., 1989 [34]	Spain	Pregnant women; (153)	Multivitamin capsules.; Supplement = 350 𝜇g folic acid, 105 mg ferrous sulphate, 500 mg ascorbic acid, daily.; Placebo = 105 mg ferrous sulphate, 500 mg ascorbic acid, daily.	FA = 75; 𝑃=78	Range: 0–350 𝜇g/day.; Duration: 25 wks.	RBC folate (𝜇g/L) (L. Casei microbiological assay).; Serum folate (𝜇g/L) (L. Casei microbiological assay).	<0.001; <0.001
Nogueira et al., 2003 [35]	Brazil	Pregnant women (114)	Mineral tablets.; Supplement = 250 𝜇g folic acid, 120 mg iron sulphate/day.; Placebo: 120 iron sulphate/day.	FA = 15; 𝑃=16	Duration: 22 wks.	Plasma folate (mg/mL) (Radioimmunoassay-Iodo125).
Houghton et al., 2006 [36]	Canada	Lactating women (69)	Folic acid capsule = 400 𝜇g/day.; [6𝑆]-5-MTHF capsule = 416 𝜇g/day.; Placebo capsule	FA = 21; MTHF = 21; 𝑃=22	Double blind.; Duration: 16 wks.; Dietary assessment	RBC (nmol/L) (from the whole-blood folate by subtracting plasma folate and correcting for hematocrit).; Plasma folate (nmol/L) (L. rhamnosus microbiological assay).; Plasma homocysteine (μmol/L) (HPLC)	FA: <0.002; MTHF: <0.0001; MTHF: <0.002
Mackey and Picciano, 1999 [20]	USA	Lactating women (42)	Folic acid capsules = 1 mg/day.; Placebo tablet	FA = 21; 𝑃=21	Double blind, folic acid tablets indistinguishable from placebo tablets.; Duration: 12 wks.; Dietary assessment	RBC folate (nmol/L) (L. Casei microbiological assay).; Plasma folate (nmol/L) (L. Casei microbiological assay).; Plasma homocysteine (𝜇mol/L) (HPLC).	<0.05

*The Authors kindly requested us to cite both the publication in AJCN [18] and Lamers’ Ph.D. thesis for the raw data [37].
RCB: red blood cell.
^aSignificant differences between the baseline and the end of the treatment.
FA: folic acid.
MTHF: methyltetrahydrofolate.